tbuckley/cabot-search huggingface dataset:
Combinatorial biomarker for predicting outcomes to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma
Authors: Julie Stein Deutsch, Evan J. Lipson, Ludmila Danilova, Suzanne L. Topalian, Jaroslaw Jedrych, Ezra Baraban, Yasser Ged, Nirmish Singla, Toni K. Choueiri, Saurabh Gupta, Robert J. Motzer, David McDermott, Sabina Signoretti, Michael Atkins, Janis M. Taube
Journal: Cell Reports Medicine (2023)

With a rapidly developing immunotherapeutic landscape for patients with metastatic clear cell renal cell carcinoma, biomarkers of efficacy are highly desirable to guide treatment strategy. Hematoxylin and eosin (H&E)-stained slides are inexpensive and widely available in pathology laboratories, including in resource-poor settings. Here, H&E scoring of tumor-infiltrating immune cells (TILplus) in pre-treatment tumor specimens using light microscopy is associated with improved overall survival (OS) in three independent cohorts of patients receiving immune checkpoint blockade. Necrosis score alone does not associate with OS; however, necrosis modifies the predictive effect of TILplus, a finding that has broad translational relevance for tissue-based biomarker development. PBRM1 mutational status is combined with H&E scores to further refine outcome predictions (OS, p = 0.007, and objective response, p = 0.04). These findings bring H&E assessment to the fore for biomarker development in future prospective, randomized trials, and emerging multi-omics classifiers.
Functional contribution of mesencephalic locomotor region nuclei to locomotor recovery after spinal cord injury
Authors: Marie Roussel, David Lafrance-Zoubga, Nicolas Josset, Maxime Lemieux, Frederic Bretzner
Journal: Cell Reports Medicine (2023)

Spinal cord injury (SCI) results in a disruption of information between the brain and the spinal circuit. Electrical stimulation of the mesencephalic locomotor region (MLR) can promote locomotor recovery in acute and chronic SCI rodent models. Although clinical trials are currently under way, there is still debate about the organization of this supraspinal center and which anatomic correlate of the MLR should be targeted to promote recovery. Combining kinematics, electromyographic recordings, anatomic analysis, and mouse genetics, our study reveals that glutamatergic neurons of the cuneiform nucleus contribute to locomotor recovery by enhancing motor efficacy in hindlimb muscles, and by increasing locomotor rhythm and speed on a treadmill, over ground, and during swimming in chronic SCI mice. In contrast, glutamatergic neurons of the pedunculopontine nucleus slow down locomotion. Therefore, our study identifies the cuneiform nucleus and its glutamatergic neurons as a therapeutical target to improve locomotor recovery in patients living with SCI.
Stimulation of the beta-2-adrenergic receptor with salbutamol activates human brown adipose tissue
Authors: Maaike E. Straat, Carlijn A. Hoekx, Floris H.P. van Velden, Lenka M. Pereira Arias-Bouda, Lauralyne Dumont, Denis P. Blondin, Mariëtte R. Boon, Borja Martinez-Tellez, Patrick C.N. Rensen
Journal: Cell Reports Medicine (2023)

While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and responsible for noradrenergic activation. Therefore, we performed a randomized double-blinded crossover trial in young lean men to compare the effects of single intravenous bolus of the ADRB2 agonist salbutamol without and with the ADRB1/2 antagonist propranolol on glucose uptake by BAT, assessed by dynamic 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan (i.e., primary outcome). Salbutamol, compared with salbutamol with propranolol, increases glucose uptake by BAT, without affecting the glucose uptake by skeletal muscle and white adipose tissue. The salbutamol-induced glucose uptake by BAT positively associates with the increase in energy expenditure. Notably, participants with high salbutamol-induced glucose uptake by BAT have lower body fat mass, waist-hip ratio, and serum LDL-cholesterol concentration. In conclusion, specific ADRB2 agonism activates human BAT, which warrants investigation of ADRB2 activation in long-term studies (EudraCT: 2020-004059-34).
Solving data quality issues of fundus images in real-world settings by ophthalmic AI
Authors: Zhongwen Li, Wei Chen
Journal: Cell Reports Medicine (2023)

Liu et al.1 develop a deep-learning-based flow cytometry-like image quality classifier, DeepFundus, for the automated, high-throughput, and multidimensional classification of fundus image quality. DeepFundus significantly improves the real-world performance of established artificial intelligence diagnostics in detecting multiple retinopathies.
An adverse tumor-protective effect of IDO1 inhibition
Authors: Juliana C.N. Kenski, Xinyao Huang, David W. Vredevoogd, Beaunelle de Bruijn, Joleen J.H. Traets, Sofía Ibáñez-Molero, Sebastiaan M. Schieven, Alex van Vliet, Oscar Krijgsman, Thomas Kuilman, Joanna Pozniak, Fabricio Loayza-Puch, Alexandra M. Terry, Judith Müller, Meike E.W. Logtenberg, Marjolein de Bruijn, Pierre Levy, Pierre-René Körner, Colin R. Goding, Ton N. Schumacher, Jean-Christophe Marine, Reuven Agami, Daniel S. Peeper
Journal: Cell Reports Medicine (2023)

By restoring tryptophan, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors aim to reactivate anti-tumor T cells. However, a phase III trial assessing their clinical benefit failed, prompting us to revisit the role of IDO1 in tumor cells under T cell attack. We show here that IDO1 inhibition leads to an adverse protection of melanoma cells to T cell-derived interferon-gamma (IFNγ). RNA sequencing and ribosome profiling shows that IFNγ shuts down general protein translation, which is reversed by IDO1 inhibition. Impaired translation is accompanied by an amino acid deprivation-dependent stress response driving activating transcription factor-4 (ATF4)high/microphtalmia-associated transcription factor (MITF)low transcriptomic signatures, also in patient melanomas. Single-cell sequencing analysis reveals that MITF downregulation upon immune checkpoint blockade treatment predicts improved patient outcome. Conversely, MITF restoration in cultured melanoma cells causes T cell resistance. These results highlight the critical role of tryptophan and MITF in the melanoma response to T cell-derived IFNγ and uncover an unexpected negative consequence of IDO1 inhibition.
Burden of fatty liver and hepatic fibrosis in persons with HIV: A diverse cross-sectional US multicenter study
Authors: Samer Gawrieh, Jordan E. Lake, Paula Debroy, Julia A. Sjoquist, Montreca Robison, Mark Tann, Fatih Akisik, Surya S. Bhamidipalli, Chandan K. Saha, Kimon Zachary, Gregory K. Robbins, Samir K. Gupta, Raymond T. Chung, Naga Chalasani, Kathleen E. Corey
Journal: Hepatology (2023)

The current prevalence of fatty liver disease (FLD) due to alcohol-associated (AFLD) and nonalcoholic (NAFLD) origins in US persons with HIV (PWH) is not well defined. We prospectively evaluated the burden of FLD and hepatic fibrosis in a diverse cohort of PWH.
Correction To: A biomimetic nanoplatform for customized photothermal therapy of HNSCC evaluated on patient-derived xenograft models
Authors: Qi Wu, Lan Chen, Xiaojuan Huang, Jiayi Lin, Jiamin Gao, Guizhu Yang, Yaping Wu, Chong Wang, Xindan Kang, Yanli Yao, Yujue Wang, Mengzhu Xue, Xin Luan, Xin Chen, Zhiyuan Zhang, Shuyang Sun
Journal: International Journal of Oral Science (2023)

Cancer cell membrane (CCM) derived nanotechnology functionalizes nanoparticles (NPs) to recognize homologous cells, exhibiting translational potential in accurate tumor therapy. However, these nanoplatforms are majorly generated from fixed cell lines and are typically evaluated in cell line-derived subcutaneous-xenografts (CDX), ignoring the tumor heterogeneity and differentiation from inter- and intra- individuals and microenvironments between heterotopic- and orthotopic-tumors, limiting the therapeutic efficiency of such nanoplatforms. Herein, various biomimetic nanoplatforms (CCM-modified gold@Carbon, i.e., Au@C-CCM) were fabricated by coating CCMs of head and neck squamous cell carcinoma (HNSCC) cell lines and patient-derived cells on the surface of Au@C NP. The generated Au@C-CCMs were evaluated on corresponding CDX, tongue orthotopic xenograft (TOX), immune-competent primary and distant tumor models, and patient-derived xenograft (PDX) models. The Au@C-CCM generates a photothermal conversion efficiency up to 44.2% for primary HNSCC therapy and induced immunotherapy to inhibit metastasis via photothermal therapy-induced immunogenic cell death. The homologous CCM endowed the nanoplatforms with optimal targeting properties for the highest therapeutic efficiency, far above those with mismatched CCMs, resulting in distinct tumor ablation and tumor growth inhibition in all four models. This work reinforces the feasibility of biomimetic NPs combining modular designed CMs and functional cores for customized treatment of HNSCC, can be further extended to other malignant tumors therapy.
Kidney health for all: preparedness for the unexpected in supporting the vulnerable
Authors: Li-Li Hsiao, Kavya M. Shah, Adrian Liew, Dina Abdellatif, Alessandro Balducci, Ágnes Haris, Latha A. Kumaraswami, Vassilios Liakopoulos, Siu-Fai Lui, Ifeoma Ulasi, Robyn G. Langham, Li-Li Hsiao, Dina Abdellatif, Alessandro Balducci, Ágnes Haris, Latha A. Kumaraswami, Vassilios Liakopoulos, Siu-Fai Lui, Ifeoma Ulasi, Robyn G. Langham, Alice Poidevin, Anne Hradsky
Journal: Kidney International (2023)

As the rate of natural disasters and other devastating events caused by human activities increases, the burden on the health and well-being of those affected by kidney disease has been immeasurable. Health system preparedness, which involves creating a resilient system that is able to deal with the health needs of the entire community during times of unexpected disruptions to usual care, has become globally important. In the wake of the COVID-19 pandemic, there is a heightened awareness of the amplification of negative effects on the renal community. Paradoxically, the complex medical needs of those who have kidney diseases are not met by systems handling crises, often compounded by an acute increase in burden via new patients as a result of the crisis itself. Disruptions in kidney care as a result of unexpected events are becoming more prevalent and likely to increase in the years to come. It is therefore only appropriate that the theme for this year's World Kidney Day will focus on Kidney Health for All: preparedness for the unexpected in supporting the vulnerable.
Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Studies
Authors: Tatsuhiko Naito, Kosuke Inoue, Kyuto Sonehara, Ryuta Baba, Takaya Kodama, Yu Otagaki, Akira Okada, Kiyotaka Itcho, Kazuhiro Kobuke, Shinji Kishimoto, Kenichi Yamamoto, Takayuki Morisaki, Yukihito Higashi, Nobuyuki Hinata, Koji Arihiro, Noboru Hattori, Yukinori Okada, Kenji Oki
Journal: Circulation (2023)

Background: Hypertension imposes substantial health and economic burden worldwide. Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, causing cardiovascular events at higher risk compared with essential hypertension. However, the germline genetic contribution to the susceptibility of PA has not been well elucidated. Method: We conducted a genome-wide association analysis of PA in the Japanese population and a cross-ancestry meta-analysis combined with UK Biobank and FinnGen cohorts (816 PA cases and 425 239 controls) to identify genetic variants that contribute to PA susceptibility. We also performed a comparative analysis for the risk of 42 previously established blood pressure–associated variants between PA and hypertension with the adjustment of blood pressure. Results: In the Japanese genome-wide association study, we identified 10 loci that presented suggestive evidence for the association with the PA risk ( P &lt;1.0×10 −6 ). In the meta-analysis, we identified 5 genome-wide significant loci (1p13, 7p15, 11p15, 12q24, and 13q12; P &lt;5.0×10 −8 ), including 3 of the suggested loci in the Japanese genome-wide association study. The strongest association was observed at rs3790604 (1p13), an intronic variant of WNT2B (odds ratio, 1.50 [95% CI, 1.33−1.69]; P =5.2×10 −11 ). We further identified 1 nearly genome-wide significant locus (8q24, CYP11B2 ), which presented a significant association in the gene-based test ( P =7.2×10 −7 ). Of interest, all of these loci were known to be associated with blood pressure in previous studies, presumably because of the prevalence of PA among individuals with hypertension. This assumption was supported by the observation that they had a significantly higher risk effect on PA than on hypertension. We also revealed that 66.7% of the previously established blood pressure–associated variants had a higher risk effect for PA than for hypertension. Conclusions: This study demonstrates the genome-wide evidence for a genetic predisposition to PA susceptibility in the cross-ancestry cohorts and its significant contribution to the genetic background of hypertension. The strongest association with the WNT2B variants reinforces the implication of the Wnt/β-catenin pathway in the PA pathogenesis.
Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment
Authors: Bo Wu, Xiang Shi, Meixi Jiang, Hongxu Liu
Journal: Molecular Cancer (2023)

Abstract Ongoing research has revealed that the existence of cancer stem cells (CSCs) is one of the biggest obstacles in the current cancer therapy. CSCs make an influential function in tumor progression, recurrence and chemoresistance due to their typical stemness characteristics. CSCs are preferentially distributed in niches, and those niche sites exhibit characteristics typical of the tumor microenvironment (TME). The complex interactions between CSCs and TME illustrate these synergistic effects. The phenotypic heterogeneity within CSCs and the spatial interactions with the surrounding tumor microenvironment led to increased therapeutic challenges. CSCs interact with immune cells to protect themselves against immune clearance by exploiting the immunosuppressive function of multiple immune checkpoint molecules. CSCs also can protect themselves against immune surveillance by excreting extracellular vesicles (EVs), growth factors, metabolites and cytokines into the TME, thereby modulating the composition of the TME. Therefore, these interactions are also being considered for the therapeutic development of anti-tumor agents. We discuss here the immune molecular mechanisms of CSCs and comprehensively review the interplay between CSCs and the immune system. Thus, studies on this topic seem to provide novel ideas for reinvigorating therapeutic approaches to cancer.
SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities
Authors: Alvaro Andrades, Paola Peinado, Juan Carlos Alvarez-Perez, Juan Sanjuan-Hidalgo, Daniel J. García, Alberto M. Arenas, Ana M. Matia-González, Pedro P. Medina
Journal: Molecular Cancer (2023)

Abstract Hematological malignancies are a highly heterogeneous group of diseases with varied molecular and phenotypical characteristics. SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes play significant roles in the regulation of gene expression, being essential for processes such as cell maintenance and differentiation in hematopoietic stem cells. Furthermore, alterations in SWI/SNF complex subunits, especially in ARID1A/1B/2, SMARCA2/4, and BCL7A, are highly recurrent across a wide variety of lymphoid and myeloid malignancies. Most genetic alterations cause a loss of function of the subunit, suggesting a tumor suppressor role. However, SWI/SNF subunits can also be required for tumor maintenance or even play an oncogenic role in certain disease contexts. The recurrent alterations of SWI/SNF subunits highlight not only the biological relevance of SWI/SNF complexes in hematological malignancies but also their clinical potential. In particular, increasing evidence has shown that mutations in SWI/SNF complex subunits confer resistance to several antineoplastic agents routinely used for the treatment of hematological malignancies. Furthermore, mutations in SWI/SNF subunits often create synthetic lethality relationships with other SWI/SNF or non-SWI/SNF proteins that could be exploited therapeutically. In conclusion, SWI/SNF complexes are recurrently altered in hematological malignancies and some SWI/SNF subunits may be essential for tumor maintenance. These alterations, as well as their synthetic lethal relationships with SWI/SNF and non-SWI/SNF proteins, may be pharmacologically exploited for the treatment of diverse hematological cancers.
The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130
Authors: Stephan A. Müller, Merav D. Shmueli, Xiao Feng, Johanna Tüshaus, Neele Schumacher, Ryan Clark, Brad E. Smith, An Chi, Stefan Rose-John, Matthew E. Kennedy, Stefan F. Lichtenthaler
Journal: Molecular Neurodegeneration (2023)

Abstract Background The protease BACE1 is a major drug target for Alzheimer’s disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates. Methods To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Results Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. Conclusion BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans. Graphical abstract
Lung cancer immunotherapy: progress, pitfalls, and promises
Authors: Aritraa Lahiri, Avik Maji, Pravin D. Potdar, Navneet Singh, Purvish Parikh, Bharti Bisht, Anubhab Mukherjee, Manash K. Paul
Journal: Molecular Cancer (2023)

Abstract Lung cancer is the primary cause of mortality in the United States and around the globe. Therapeutic options for lung cancer treatment include surgery, radiation therapy, chemotherapy, and targeted drug therapy. Medical management is often associated with the development of treatment resistance leading to relapse. Immunotherapy is profoundly altering the approach to cancer treatment owing to its tolerable safety profile, sustained therapeutic response due to immunological memory generation, and effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground in the treatment of lung cancer. Recent advances in adoptive cell therapy (CAR T, TCR, TIL), the associated clinical trials on lung cancer, and associated hurdles are discussed in this review. Recent trials on lung cancer patients (without a targetable oncogenic driver alteration) reveal significant and sustained responses when treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that a loss of effective anti-tumor immunity is associated with lung tumor evolution. Therapeutic cancer vaccines combined with immune checkpoint inhibitors (ICI) can achieve better therapeutic effects. To this end, the present article encompasses a detailed overview of the recent developments in the immunotherapeutic landscape in targeting small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Additionally, the review also explores the implication of nanomedicine in lung cancer immunotherapy as well as the combinatorial application of traditional therapy along with immunotherapy regimens. Finally, ongoing clinical trials, significant obstacles, and the future outlook of this treatment strategy are also highlighted to boost further research in the field.
Elevated Levels of Interferon‐α Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production
Authors: Dario M. Ferri, Carol Nassar, Kieran P. Manion, Michael Kim, Yuriy Baglaenko, Carolina Muñoz‐Grajales, Joan E. Wither
Journal: Arthritis & Rheumatology (2023)

Elevated levels of serum interferon-α (IFNα) and the disruption of B cell tolerance are central to systemic lupus erythematosus (SLE) immunopathogenesis; however, the relationship between these 2 processes remains unclear. The purpose of this study was to investigate the impact of elevated IFNα levels on B cell tolerance mechanisms in vivo and determine whether any changes observed were due to the direct effect of IFNα on B cells.Two classical mouse models of B cell tolerance were used in conjunction with an adenoviral vector encoding IFNα to mimic the sustained elevations of IFNα seen in SLE. The role of B cell IFNα signaling, T cells, and Myd88 signaling was determined using B cell-specific IFNα receptor-knockout, CD4+ T cell-depleted, or Myd88-knockout mice, respectively. Flow cytometry, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and cell cultures were used to study the effects of elevated IFNα on the immunologic phenotype.Elevation of serum IFNα disrupts multiple B cell tolerance mechanisms and leads to autoantibody production. This disruption was dependent upon B cell expression of IFNα receptor. Many of the IFNα-mediated alterations also required the presence of CD4+ T cells as well as Myd88, suggesting that IFNα acts directly on B cells to modify their response to Myd88 signaling and their ability to interact with T cells.The results provide evidence that elevated IFNα levels act directly on B cells to facilitate autoantibody production and further highlight the importance of IFN signaling as a potential therapeutic target in SLE.